This overall goal of this research program is to develop new synthesis strategies and methods and use them to characterize the channel-based mechanism of action of amphotericin B (AmB) in atomistic detail, thereby enabling the rational optimization of the therapeutic index of this clinically-vital but also highly toxic antimycotic agent. Computer modeling studies predict that certain protic functional groups appended to the natural product are critical for self-assembly of the AmB/cholesterol channel (which leads to toxicity) but are not critical for the AmB/ergosterol channel (which leads to antifungal activity), thus leading to the following hypothesis: improvements in the therapeutic index of AmB can be achieved via the selective deletion of one or more of these protic functional groups. This research program aims to test this hypothesis systematically. New synthetic strategies and methods will be developed to enable the twelve protic functional groups appended to amphotericin B to be """"""""deleted"""""""", one at a time. Analogous to the process of alanine scanning in protein science, the consequences of each protic functional group deletion will be determined in a battery of biophysical and biological assays. Statement in lay language: The antibiotic called """"""""amphotericin"""""""" is the most effective medicine currently available for the treatment of life- threatening fungal infections. Unfortunately, however, this drug has many toxic side-effects that often limit its efficacy. This research program aims to understand more clearly how amphotericin works and minimize these toxic side-effects using a combination of organic synthesis and biological assays.
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| Gonzalez, Jorge A; Ogba, O Maduka; Morehouse, Gregory F et al. (2016) MIDA boronates are hydrolysed fast and slow by two different mechanisms. Nat Chem 8:1067-1075 |
| Davis, Stephen A; Vincent, Benjamin M; Endo, Matthew M et al. (2015) Nontoxic antimicrobials that evade drug resistance. Nat Chem Biol 11:481-7 |
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| Li, Junqi; Grillo, Anthony S; Burke, Martin D (2015) From synthesis to function via iterative assembly of N-methyliminodiacetic acid boronate building blocks. Acc Chem Res 48:2297-307 |
| Cioffi, Alexander G; Hou, Jennifer; Grillo, Anthony S et al. (2015) Restored Physiology in Protein-Deficient Yeast by a Small Molecule Channel. J Am Chem Soc 137:10096-9 |
| Davis, Stephen A; Della Ripa, Lisa A; Hu, Lingbowei et al. (2015) C3-OH of Amphotericin B Plays an Important Role in Ion Conductance. J Am Chem Soc 137:15102-4 |
| Anderson, Thomas M; Clay, Mary C; Cioffi, Alexander G et al. (2014) Amphotericin forms an extramembranous and fungicidal sterol sponge. Nat Chem Biol 10:400-6 |
| Woerly, Eric M; Roy, Jahnabi; Burke, Martin D (2014) Synthesis of most polyene natural product motifs using just 12 building blocks and one coupling reaction. Nat Chem 6:484-91 |
| Woerly, Eric M; Miller, Jonathan E; Burke, Martin D (2013) (1-bromovinyl)-MIDA boronate: a readily accessible and highly versatile building block for small molecule synthesis. Tetrahedron 69: |
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